The goal of this application is to develop and characterize novel vaccine carriers to HIV-1 antigens based on El-deleted adenoviral recombinants derived from chimpanzee serotypes in pre-clinical animal models. Such serotypes of adenovirus do not circulate in the human population. They should induce responses to the HIV-1 antigens that are unimpaired by pre-existing neutralizing antibodies to the vaccine carrier. Such antibodies are expected to reduce the efficacy of vaccines based on common human serotypes of adenovirus in a human target population. Projects 1 and 2 will generate additional vaccine carriers for booster immunizations. Project I will generate recombinants derived from alternate chimpanzee serotypes (C5, C6 or C7). This Project will also construct a molecular clone for the chimpanzee serotype 68 of adenovirus (AdC68) and other viruses that will be developed further as vaccines to facilitate the generation of recombinants free of potential contaminants. Project 2 will focus on the hexon of AdC68 virus, and generate artificial serotypes by site-directed mutagenesis using structural information from X-ray crystallography and modeling as well as epitope mapping of virus neutralizing antibodies. Project 3 will test the already developed vaccines based on AdC68 virus, as well as the novel constructs developed by Projects 1 and 2, for induction of immune responses to gag/pol/nef and gp140 of HIV-1 clades B and C in rodents. Project 4 will test SIVmac239 gag/pol/nef or HIV-1 gp140 clade C constructs for induction of T and B cell responses and protection to SHIV89.6P, SIVmac231 or a newly-developed clade C SHIV challenge in non-human primates. Two Cores will support the Program. Core 1 is an Administrative Core, while Core 2 is a Vector Core that will provide the investigators of Projects 1-4 with adenoviral recombinants.